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The eye is a spectacular sensory organ, known to be sophisticated. These last years, ophthalmology and ophtalmopharmacology have strongly progressed due to technological advances. For topically administered drugs, the first structure affected is the cornea. Therefore it forms the primary rate-limiting permeability barrier to compound absorption into the anterior chamber of the eye. Ocular drug absorption into anterior ocular tissue is determined either by passive diffusion, facilitated diffusion or by active transport. The scientific literature gives us information about the expression of many transporters in the corneal epithelium which can act as drug delivery system. We can classify transporters both as influx or efflux transporters. Efflux transporters include MRP1 4,5,6 and MDR1. They play an important role in the protection of ocular tissue, indeed, the mechanism of efflux enhance ocular drug penetration. Influx transporters include peptides transporters such as PEPTs, ATB0, +, LAT They may be particularly important in absorption, distribution and clearance of their drug substrate in the eye. The discovery of such transporters in the corneal epithelium is an interesting theme of research that cans enrich the field of ophatlmopharmacology. Indeed, understanding the substrate specificity and the structure- activity relationships of various transporter proteins might make it possible to design prodrugs that are targeted to specific transporter. This point of view is very important to develop new drugs which could treat ocular pathologies such as inflammations, infections and glaucoma. Research about cornea transporters move forward and continue to grow. It is evident that the knowledge about this subject is currently quite limited. Extensive studies are needed to clarify the role and clinical significance of drug transporters in the eye but the future is promising in this regard L’œil est un organe sensoriel spectaculaire et étonnamment sophistiqué. Ces dernières années, les avancées technologiques ont permis de faire des progrès considérables en ce qui concerne l’ophtalmologie et l’ophtalmopharmacologie. Lors de l’application topique de substances actives au niveau de l’œil, la première structure touchée est la cornée. Celle-ci forme une barrière limitante et perméable à l’absorption de substances actives au niveau de la chambre antérieure de l’œil. L’absorption de tels composés se fait donc selon différents phénomènes, tels qu’un transport passif, actif ou encore un transport facilité. L’analyse de la littérature scientifique nous apprend que la cornée exprime de façon non négligeable des transporteurs. On y retrouve des transporteurs à efflux tels que le MRP1,4,5,6, MDR1, qui jouent un rôle important au niveau de la protection des tissus oculaires, en empêchant toute pénétration de substance active. On retrouve également des transporteurs à influx de type peptidiques comme les PEPTs, ATB0, +, LAT, etc... Ceux-ci sont étroitement impliqués dans l’absorption, la distribution et la clairance d’un principe actif au niveau de l’œil. La découverte de ces transporteurs au niveau de la cornée offre une cible de recherche très intéressante et apporte ainsi une réelle avancée dans le domaine de l’ophtalmopharmacologie. En effet, en connaissant la spécificité des substrats et les relations de structure-activité entre le substrat et divers transporteurs, on peut facilement imaginer la création de prodrogues qui cibleraient de manière spécifique les transporteurs, où comment transformer une molécule incapable de traverser un transporteur en un substrat idéal? Ceci est particulièrement intéressant pour les pathologies oculaires telles que les inflammations, les infections et le glaucome. La recherche sur les transporteurs de la cornée va de l’avant et ne cesse de progresser. Cependant, les connaissances à ce sujet restent limitées et d’autres études sont nécessaires pour clarifier le rôle et l’importance clinique de ces transporteurs

Eye --- Epithelium, Corneal --- Membrane Transport Proteins --- Opthalmology

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Participant à laplupartdes transmissions excitatrices, le glutamate est un essentiel au sein du système nerveux central. Cependant, il doit impérativement être éliminé de la fente synaptique, afin d'éviter des phénomènes de neurotoxicité. Cette élimination est principalement assurée par les astrocytes, qui expriment des transporteurs membranaires spécifiques. Dans les tumeurs gliales (gliomes), cette homéostasie glutamatergique est fortement perturbée. Malgré leur origine souvent astrocytaire, les cellules de gliome sont incapables de capter efficacement le glutamate et, au contraire, en libèrent des quantités importantes. Les processus biochimiques régulant les transporteurs du glutamate dans le gliome restent peu documentés. Des expériences réalisées sur des modèles recombinants proposent que la kinase activée par I'AMP (AMPK) soit capable de réguler le transport du glutamate. En outre, des études en cours au sein de notre laboratoire suggèrent que cette kinase exerce une influence sur le transport du glutamate dans des astrocytes en culture primaire. Puisque I'AMPK semble être impliquée dans la progression de divers cancers, nous avons examiné le lien éventuel entre le degré d'activation constitutive de cette enzyme dans une lignée d'astrocytome, les cellules C6, et leur faible capacité à capter le glutamate. Nous avons d'abord déterminé que I'AMPK est constitutivement plus active dans notre modèle de gliome comparativement au modèle astrocytaire. Ensuite, par le biais de la différenciation astrocytaire forcée de cette lignée de gliome, nous avons montré qu'il est possible de réprimer l'activité constitutive de l'AMPK et de diminuer également l'expression de sa sous-unité catalytique al. Cette perte d'activité de l'AMPK s'est accompagnée d'une augmentation du transport du glutamate dans ces cellules en différenciation. Finalement, la manipulation génétique de l'expression de l’AMPKα1 s'est également révélée capable d'augmenter le transport du glutamate dans le modèle de gliome, appuyant ainsi notre hypothèse. La consolidation de ces travaux reste, cependant, nécessaire afin préciser la relevance de ces observations dans le développement du gliome. Glutamate is the principal excitatory neurotransmitter in the nervous system. However, elevated extracellular concentrations of this transmitter seem to be an important cause of neuronal death in a variety of nervous system diseases. Therefore, tight regulation of glutamate concentrations is important for normal brain function and is mainly ensured by glial cells, which express high affinity glutamate transporters. ln glia-derived tumors (gliomas), glutamate homeostasis was proven to be disrupted and this correlates with a reduced expression of specific glutamate transporters. ln fact, these cells are unable to efficiently take up glutamate from the synaptic cleft, leading to excitotoxicity in the vicinity of the tumor, thus potentially favoring tumor progression. However, the mechanisms regulating glutamate transporters in glial tumors remain unknown. Previous studies performed on recombinant models suggest that the cellular energy sensor AMP-activated protein kinase (AMPK) influences the activity of glutamate transporters. Moreover, recent work in our laboratory indicates that AMPK activation promotes a decrease of cell-surface expression of glutamate transporters, in primary cultures of astrocytes. Given that AMPK has been implicated in the progression of several tumors, we here propose the hypothesis for a functional link between the constitutive activation of AMPK previously reported in glial tumors, and the impaired glutamate uptake capacity of these cancer cells. Firstly, our data showed that the AMPK activity found in a rat glioma model (C6 cell line) is constitutively higher when compared to normal rodent astrocytes. Secondly, by driving differentiation of the glioma cell line into an astrocytic phenotype, we were able to reduce this constitutive AMPK activity and the expression of its al catalytic subunit. These changes were correlated with an increased activity and expression of glutamate transporters in C6 cells undergoing differentiation. Thirdly, preliminary results showed that genetic manipulation of AMPKα1 expression in naïve C6 cells promotes their glutamate uptake capacity. Together, our data suggest a putative link between the constitutive AMPK activity observed in glioma cells and their impaired capacity to take up glutamate. Further studies, including the analysis of other glioma cell lines and human glioma samples, should help to consolidate our hypothesis.

AMP-Activated Protein Kinases --- Glutamate Plasma Membrane Transport Proteins --- Glioma

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Ion Channels --- Muscles --- Potassium --- Sodium --- Biological Transport. --- Biologic Transport --- Transport, Biological --- Transport, Biologic --- Transport Vesicles --- Membrane Transport Proteins --- physiology. --- metabolism. --- Theses --- Biological Transport --- physiology --- metabolism

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Plant physiology --- membranes --- Vacuoles --- plant nutrition --- Storage organs --- Plant cell membranes --- Plant translocation --- Calcium --- Iron --- Manganese --- Membrane transport proteins --- Metals, heavy --- Nitrogen --- Photosynthesis --- Plants --- Potassium --- Silicon --- Sulfates

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The discipline of Synthetic Biology has recently emerged at the interface of biology and engineering. The definition of Synthetic Biology has been dynamic over time ever since, which exemplifies that the field is rapidly moving and comprises a broad range of research areas. In the frame of this Research Topic, we focus on Synthetic Biology approaches that aim at rearranging biological parts/ entities in order to generate novel biochemical functions with inherent metabolic activity. This Research Topic encompasses Pathway Engineering in living systems as well as the in vitro assembly of biomolecules into nano- and microscale bioreactors. Both, the engineering of metabolic pathways in vivo, as well as the conceptualization of bioreactors in vitro, require rational design of assembled synthetic pathways and depend on careful selection of individual biological functions and their optimization. Mathematical modelling has proven to be a powerful tool in predicting metabolic flux in living and artificial systems, although modelling approaches have to cope with a limitation in experimentally verified, reliable input variables. This Research Topic puts special emphasis on the vital role of modelling approaches for Synthetic Biology, i.e. the predictive power of mathematical simulations for (i) the manipulation of existing pathways and (ii) the establishment of novel pathways in vivo as well as (iii) the translation of model predictions into the design of synthetic assemblies.

Metabolic Engineering --- reconstitution --- molecular dynamics simulations --- Membrane Transport Proteins --- Protein Engineering --- Protein scaffolds --- metabolite profiling --- Interaction domains --- Metabolic Modelling --- Starch biosynthesis